Review of alternative macrocyclization methods for the synthesis of macrolides

Abstract

Macrolides, macrocyclic lactones containing at least a ring of twelve members, present many interesting features, such as antibiotic, antifungal or anticancer activities, among others. Isolation from natural sources often provides limited quantities of these compounds. Therefore there is great interest in the consecution of their total syntheses. A key step in their preparation is cyclization, since it is often a challenging step. The most common method to form the ring is macrolactonization, although, in recent years, ring-closing metathesis has also been used by many research groups. However, these methods are not always appropriate for all macrolides, depending on their size and structure. In this report, an exhaustive bibliographic search has been undertaken to analyze which alternative methods are being used most often to cyclize these compounds. SciFinder and Reaxys are the databases that have been chosen for this search during the period 2012 to 2017. Several methods have been identified. Apart from macrolatonizations and ring-closing metathesis, the most popular are cross-coupling methods and olefinations. The use of the most common alternatives for the total synthesis of natural product macrolides in the period 2012–2017 has been reviewed